This proposal addresses the broad subject area, Biomarker Discovery and Validation and the specific challenge topic, Biomarkers of Persistent Damage After Acute Joint Injury (03-AR-101). Our proposal entitled "Biomarkers of the Risk for Post-Traumatic Osteoarthritis" addresses an urgent need to identify molecular markers related to the processes that drive post-traumatic osteoarthritis in articular fracture patients. The intensity of the initial joint trauma in intra-articular fractures is a critically important factor in the risk for post-traumatic osteoarthritis (OA). Interventions to surgically reduce the displaced and fragmented articular surface have been developed and refined over decades. Yet, for some injuries, post- traumatic OA remains seemingly inevitable, with surgical advances unlikely to appreciably change the prognosis. Little is known regarding the biological processes at work within the joint shortly following these injuries, or how they specifically link joint injury to eventual post- traumatic OA. A novel CT-based metric has enabled, for the first time, quantitative evaluation of articular fracture severity. It has been used to show that the severity of tibial plafond fractures positively correlates with the subsequent occurrence of ankle OA. The power that this new tool affords to stratify articular fractures according to their severity opens new opportunities to identify and validate molecular biomarkers, which are needed to guide the development of treatments to prevent post-traumatic OA. With that in mind we propose to determine the relationships between CT-derived injury severity measures and the kinetics of release of serum and urinary biomarkers related to bone and cartilage damage and repair in ankle fracture patients. In follow-up studies we will determine how biomarkers that reflect injury severity relate to the development of post-traumatic OA. A limitation of the approach described above is that the relationship between fracture severity and arthritis is subject to biologic variations that affect recovery from injury, which are likely to influence the threshold severity that leads to post-traumatic osteoarthritis. Thus, biomarkers that reflect injury severity alone may underestimate the risk for post-traumatic osteoarthritis, particularly in patients from near the middle of the severity spectrum. To begin to address this issue we propose to study metabolic biomarkers that have been shown to predict the potential for fracture repair. This project takes advantage of an innovation in imaging technology to help identify molecular biomarkers of the risk for post-traumatic OA. The results of this research are expected to provide early warning of post-traumatic OA in ankle fracture patients, information that may be used to modify treatment and rehabilitation. Moreover, the findings will help to elucidate biologic processes that play a role in the early post-injury pathogenesis of post- traumatic osteoarthritis, which may be subject to pharmacologic intervention. The prognostic value of the biomarkers identified in this small scale exploratory study will be further investigated in future multicenter studies with larger numbers of subjects and longer term follow ups. Our proposal entitled "Biomarkers of the Risk for Post-Traumatic Osteoarthritis" addresses an urgent need to identify molecular markers related to the processes that drive post-traumatic osteoarthritis in articular fracture patients. The results are expected to serve as the basis for the development of therapies to block the progression of post-traumatic osteoarthritis, which has an adverse impact on physical and psychological well being comparable to that of other major disorders such as stroke, heart disease, or diabetes.